CHAPTER 5
Authors: Kailash Jindal, Christopher T. Chan, Clement Deziel, David Hirsch, Steven D. Soroka, Marcello Tonelli, Bruce F. Culleton
Journal: Journal of the American Society of Nephrology (2006)

Introduction There is an emerging body of evidence which suggests that frequent hemodialysis may provide significant clinical advantages for patients with end-stage renal disease (ESRD) over conventional hemodialysis (CvHD). The aim of this chapter is to provide a rational, evidence-based approach for the clinical use of frequent hemodialysis. For the purpose of this chapter, short daily hemodialysis (SDHD) is defined as hemodialysis prescribed at 5 to 6 sessions per week, 2 to 3 h of treatment per session. Nocturnal hemodialysis (NHD) is defined as hemodialysis prescribed at 5 to 6 sessions per week during sleep, 6 to 8 h treatment per session. The location of renal replacement therapy has not been specified. SDHD is most commonly administered in-center, whereas NHD is usually provided at a home setting but not exclusively. As there is also ongoing interest in sustained treatment hemodialysis and such practice is showing resiliency, we will provide a rational, evidence-based approach for the clinical use of sustained hemodialysis. Thrice-weekly sustained hemodialysis (TWSHD) is defined as hemodialysis prescribed at 3 sessions per week, >4 h treatment per session. I. Assessment of Adequacy and Dose of Frequent and Sustained Hemodialysis Recommendations Consider control of clinical parameters, including blood pressure (BP), extracellular fluid volume control, anemia, mineral metabolism, and nutritional status when evaluating for dialysis adequacy. (Grade D, opinion) Background SDHD, NHD, and TWSHD deliver enhanced small solute clearance in comparison to conventional therapies. Although multiple dosing constructs based on urea kinetics have been proposed, none have been validated (1–3). Furthermore, the optimal dose of frequent or of sustained hemodialysis has not been defined. Although it is clear that all forms of intensive hemodialysis will exceed the current recommended guideline of hemodialysis adequacy, there is no available evidence for a specific target. In addition to urea kinetics, clinicians must consider clinical indicators (i.e., BP, extracellular fluid volume control, anemia management, control of mineral metabolism, nutritional status, and overall cardiovascular health) when using frequent or sustained hemodialysis. Clinicians should consider adjusting duration and frequency of dialysis to provide the best possible clinical outcome while balancing patient burden, quality of life, and costs. II. Clinical Indications for the Use of Frequent and Sustained Hemodialysis Recommendations In patients with poorly controlled BP, consider the use of frequent hemodialysis (Grade D) or sustained hemodialysis. (Grade C) In patients with significant left ventricular hypertrophy or impaired left ventricular systolic function, consider the use of frequent hemodialysis as adjunctive therapy. (Grade D) In patients who exhibit hemodynamic instability with conventional hemodialysis, the use of frequent hemodialysis should be considered. (Grade D, opinion) Background Hypertension is an adverse prognosticator in patients with ESRD (4). SDHD (5) and NHD (6) have been shown to improve BP control in observational studies. TWSHD has been shown to improve BP control in one randomized study (7) and in numerous observational studies (8–15). Current evidence suggests that SDHD lowers BP by decreasing extracellular fluid volume (3). In contrast, NHD decreases BP in patients with ESRD primarily via lowering total peripheral resistance (16). In addition, NHD has been documented to augment flow-mediated dilation (16), which suggests that intensive hemodialysis may have a protective vascular effect. In line with this observation, reduced vascular resistance and phenomena other than volume contraction underlying lower BP have been documented in TWSHD (7,17,18). Further research is required to elucidate the impact of frequent or of sustained dialysis on BP control and clinical outcomes using long-term, prospective, controlled studies. Left ventricular hypertrophy (LVH) and left ventricular systolic dysfunction are potent cardiovascular risk factors in patients with ESRD (19). To date, numerous medical approaches have been attempted to improve cardiac geometry and systolic function in ESRD patients with limited success (20). NHD and SDHD have been shown in nonrandomized clinical studies to be associated with regression of LVH (5,6,21). NHD was documented in a small clinical series to restore impaired left ventricular systolic function (22). The use of frequent hemodialysis may allow improved control of left ventricular geometry and systolic function. Further research is required to examine the magnitude and impact of both SDHD and NHD on these potent cardiovascular surrogate endpoints. There is no study of LVH regression with TWSHD. Furthermore, there is a high prevalence of LVH in many observational studies of TWSHD (12,13,23). Hemodynamic instability during conventional hemodialysis is not uncommonly encountered. Usual manifestations include severe leg cramping and intradialytic hypotension (24). Conversion to frequent hemodialysis has been shown to improve patients’ overall sense of well-being (25). Of note, intra- and interdialytic hemodynamic instability were greatly improved upon conversion to frequent hemodialysis (26). In the London Daily/Nocturnal Hemodialysis Study, it was reported that intradialytic symptoms decreased with the use of SDHD or NHD. It is interesting to note that the time required to recover from dialysis therapy was substantially lower with frequent hemodialysis in comparison to conventional hemodialysis. It has been suggested that frequent hemodialysis decreased the potential for intra- and interdialytic hemodynamic instability because of the lack of rapid removal of fluid in excess of interstitial refilling (27). More research is needed to optimally titrate the hemodynamic profile of ESRD patients with the use of frequent hemodialysis. With respect to TWSHD, one randomized crossover study comparing 4-h versus 5-h sessions in TWSHD found less intradialytic and postdialytic hypotension with the longer session, but an increase in other peridialytic symptoms (28). In patients with refractory hyperphosphatemia and/or secondary hyperparathyroidism, consider the use of NHD as adjunctive therapy. (Grade D, opinion) In patients with refractory peripheral vascular disease and ectopic calcification, consider the use of NHD as salvage therapy. (Grade D, opinion) In patients who exhibit chronic malnutrition, consider the use of frequent hemodialysis as salvage therapy. (Grade D, opinion) Hyperphosphatemia and secondary hyperparathyroidism in conjunction with hypercalcemia have emerged as important contributors to vascular calcification and cardiovascular death in the ESRD population (29–31). Normalization of phosphate balance and superior control of secondary hyperparathyroidism has been shown by NHD in an observational study (32). SDHD has not resulted in a comparable decrease in phosphate level as seen in NHD. The longitudinal impact of enhanced control of phosphate and lowering of parathyroid hormone axis by NHD on vascular biology and renal osteodystrophy remains to be clarified. Peripheral vascular disease remains a leading cause of cardiovascular morbidity and mortality in the ESRD population. Thus far, medical therapy has not resulted in significant success in the improvement of uremia-associated peripheral vascular disease (33). Improvement in peripheral vascular flow as measured by arterial Doppler was documented in one patient after conversion from CvHD to NHD (34). It is plausible that any improvement in peripheral vascular disease may occur through resolution of ectopic calcification, which has been reported with the use of NHD (35). It is proposed that normalization of phosphate balance in conjunction with augmentation of uremia control facilitates the resorption of ectopic calcification. There is no published data documenting the impact of SDHD on peripheral vascular disease in ESRD. Impaired nutritional parameters, including lean body mass, serum albumin, and protein intake, continue to be potent predictors of clinical outcome in ESRD patients (36,37). Observational studies suggest that frequent hemodialysis improves nutritional status of ESRD patients despite a theoretical concern of overdialysis of water-soluble nutrients (38). SDHD has been shown to improve albumin, lipid status, and protein anabolism (39–42). Similarly, NHD improves nitrogen balance, lipid status, and dietary intake in ESRD patients (41,43,44). Current evidence on the impact of frequent hemodialysis on malnutrition is limited by its observational nature and short duration of follow-up. The paucity of long-term or controlled evidence reflects the importance of further research in this domain. Recommendations for Research There is growing enthusiasm for the routine clinical use of frequent hemodialysis. It is important to note that there has not yet been any randomized controlled data to support the use of SDHD or NHD (45). Thus far, frequent hemodialysis shows early promise in improving clinical outcomes in ESRD patients. Correction of sleep apnea (46), improvement in cardiac autonomic balance (16), and amelioration of homocysteine level (47) continue to suggest that augmentation of uremic clearance is associated with improved surrogate endpoints, especially with NHD. By providing enhanced clearance, frequent hemodialysis represents a unique opportunity for the renal community to gain further insights into the basic science of uremia and its impact on other body systems. The true clinical effect of frequent hemodialysis can only be elucidated by a longitudinal, controlled, clinical study. Finally, the widespread implementation of frequent hemodialysis may only be achieved if barriers in cost, social perception, and hemodialysis training are studied in a systematic manner. Interest in TWSHD stems from sometimes exceptional survival data and BP management in mostly uncontrolled populations. As incremental hemodialysis is gaining popularity and because some patients may accept overnight sustained hemodialysis but not on a daily basis, it is important that such endeavors be explored in a rigorous, prospective manners. NHD provides not only frequent but also sustained hemodialysis compared with CvHD. Dialysis duration is readily recognized as a critical factor for water removal independent of Kt/V urea. The time dependence of uremic toxins other than water, like phosphate, and of surrogate markers of survival, like LVH, needs to be studied.